Tau protein (neurofibrillary tangles)

Tau is a microtubule-associated protein that, in Alzheimer's disease, becomes abnormally hyperphosphorylated and aggregates intracellularly into paired helical filaments that form neurofibrillary tangles (NFTs) - one of the two pathologies (with amyloid beta plaques) required for a neuropathological diagnosis of Alzheimer's disease. Tangles accumulate and spread through the brain in a stereotyped anatomical sequence (Braak staging), which is why tau PET, unlike amyloid PET, can track disease stage and distribution rather than simple positive/negative status.

Flortaucipir F18 (Tauvid) binds aggregated PHF-tau with a dissociation constant of 0.57 nM in vitro and shows negligible binding to beta-amyloid, so it reports tangle pathology specifically. It was FDA-approved in May 2020, the first and to date only approved tau PET tracer, for estimating the density and distribution of NFTs in adults with cognitive impairment being evaluated for Alzheimer's disease; it is explicitly not indicated for chronic traumatic encephalopathy, because non-Alzheimer's tauopathies show different tau conformations that the tracer does not reliably detect. Some off-target binding to monoamine oxidase A/B occurs, seen in the choroid plexus, striatum and brainstem, and is excluded from image interpretation.

As a target, tau's strength is that its regional distribution tracks clinical stage and correlates better with cognitive decline than amyloid burden does. Its main limitation is that flortaucipir's sensitivity is lower in earlier-stage disease (the pivotal studies enrolled mostly terminally ill patients with advanced NFT pathology), and it cannot distinguish Alzheimer's tau from other tauopathies.